Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H2O2- production

Nat Neurosci. 2020 Dec;23(12):1555-1566. doi: 10.1038/s41593-020-00735-y. Epub 2020 Nov 16.


Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Alzheimer Disease / psychology
  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology*
  • Atrophy
  • Brain / pathology
  • Cell Death
  • Cognitive Dysfunction / pathology
  • Disease Models, Animal
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Macrophage Activation
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Monoamine Oxidase / metabolism
  • Nerve Degeneration / pathology
  • Neuroglia
  • Neurons / pathology
  • Spatial Memory
  • Tauopathies / pathology


  • Hydrogen Peroxide
  • Monoamine Oxidase